The neuronal nicotinic receptors (NNRs) characteristic of the central nervous system (CNS) have been shown to occur in several subtypes, the most common of which are the α4β2 and α7 subtypes. See, for example, Schmitt, Current Med. Chem. 7: 749 (2000), herein incorporated by reference. Ligands that interact with the α7 NNR subtype have been proposed to be useful in the treatment of a variety of conditions and disorders. See Mazurov et al., Curr. Med. Chem. 13: 1567-1584 (2006) and references therein herein incorporated by reference with regard to background understanding of the α7 neuronal nicotinic receptor subtype. Prominent among those conditions and disorders are cognitive impairment, schizophrenia, inflammation, angiogenesis, neuropathic pain, and fibromyalgia.
There are a decreased number of hippocampal NNRs in postmortem brain tissue of schizophrenic patients. Also, there is improved psychological effect in smoking versus non-smoking schizophrenic patients. Nicotine improves sensory gating deficits in animals and schizophrenics. Blockade of the α7 NNR subtype induces a gating deficit similar to that seen in schizophrenia. See, for example, Leonard et al., Schizophrenia Bulletin 22(3): 431 (1996), herein incorporated by reference. Biochemical, molecular, and genetic studies of sensory processing in patients with the P50 auditory-evoked potential gating deficit suggest that the α7 NNR subtype may function in an inhibitory neuronal pathway. See, for example, Freedman et al., Biological Psychiatry 38(1): 22 (1995), incorporated by reference.
More recently, α7 NNRs have been proposed to be mediators of angiogenesis, as described by Heeschen et al., J. Clin. Invest. 100: 527 (2002), incorporated by reference. In these studies, inhibition of the α7 subtype was shown to decrease inflammatory angiogenesis. Also, α7 NNRs have been proposed as targets for controlling neurogenesis and tumor growth (Utsugisawa et al., Molecular Brain Research 106(1-2): 88 (2002) and U.S. Patent Application 2002/0016371, each incorporated by reference). Finally, the role of the α7 subtype in cognition (Levin and Rezvani, Current Drug Targets: CNS and to Neurological Disorders 1(4): 423 (2002)), neuroprotection (O'Neill et al., Current Drug Targets: CNS and Neurological Disorders 1(4): 399 (2002) and Jeyarasasingam et al., Neuroscience 109(2): 275 (2002)), and neuropathic pain (Xiao et al., Proc. Nat. Acad. Sci. (US) 99(12): 8360 (2002)) has recently been recognized, each citation herein incorporated by reference.
Various compounds have been reported to interact with α7 NNRs and have been proposed as therapies on that basis. See, for instance, PCT WO 99/62505, PCT WO 99/03859, PCT WO 97/30998, PCT WO 01/36417, PCT WO 02/15662, PCT WO 02/16355, PCT WO 02/16356, PCT WO 02/16357, PCT WO 02/16358, PCT WO 02/17358, Stevens et al., Psychopharm. 136: 320 (1998), Dolle et al., J. Labelled Comp. Radiopharm. 44: 785 (2001) and Macor et al., Bioorg. Med. Chem. Lett. 11: 319 (2001) and references therein, such references incorporated by reference with regard to background teaching of α7 NNRs and proposed therapies. Among these compounds, a common structural theme is that of the substituted tertiary bicyclic amine (e.g., quinuclidine). Similar substituted quinuclidine compounds have also been reported to bind at muscarinic receptors. See, for instance, U.S. Pat. Nos. 5,712,270 to Sabb and PCTs, WO 02/00652 and WO 02/051841, each of which is incorporated by reference with regard to such compounds.
A limitation of some nicotinic compounds is that they are associated with various undesirable side effects, for example, by stimulating muscle and ganglionic receptors. There continues to be a need for compounds, compositions, and methods for preventing or treating various conditions or disorders, such as CNS disorders, including alleviating the symptoms of these disorders, where the compounds exhibit nicotinic pharmacology with a beneficial effect, namely upon the functioning of the CNS, but without significant associated side effects. There is a need for compounds, compositions, and methods that affect CNS function without significantly affecting those nicotinic receptor subtypes which have the potential to induce undesirable side effects, such as appreciable activity at cardiovascular and skeletal muscle sites. The present invention provides such compounds, compositions, and methods.